DETAILED ACTION
Election/Restrictions
Applicant’s election of Group I, claims 1-3, 6-12, 14, 28 (fusion protein), 29, 34, 39 and 40; and SEQ ID NO: 2, in the reply filed on 2/20/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 16, 19, 23, 27, 28 (nucleic acid), and 33, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
The claims have been examined based on elected SEQ ID NO: 2.
SEQ ID NO: 2 is an exemplary cholera MEFA amino acid sequence containing TcpA (01 El Tor biotype), TcpA (01 Classical biotype), CTA, FlaB, CTB, LPS (SEQ ID NO: 15), Neu, HlyA, FlaC/D, and LPS (SEQ ID NO: 23) epitopes. See page 8, lines 21-31 of the instant specification for the full sequence.
SEQ ID NO: 4 is an exemplary consensus amino acid sequence for backbone protein, where 'X' indicates a location for insertion or substitution of an epitope. The indicated size of the insertion or substitution is not limiting, and can be varied.
In the Species Requirement mailed on 2/20/26, Applicants were directed to elect either a backbone protein at least 90% identical to SEQ ID NO: 4 and a specific epitope, e.g., and SEQ Id no. 6 and 10; OR seq id no: 31; etc. OR to elect the SEQ ID NO: 2 fusion protein. Applicants elected SEQ ID NO: 2.
Claim Objections
Claims 1-3, 6-12, 28 (fusion protein), 29, 34, 39 and 40 are objected to because Applicant elected SEQ ID NO: 2; yet part (i) of claim 1 comprising SEQ ID NO: 2 was deleted. Only claim 14 recites elected SEQ ID NO: 2. Instead of issuing a non-compliant amendment, the Examiner is examining the claims on the basis of the elected sequence. The bolded below was elected.
1. (Currently Amended) A fusion protein, comprising: (i) an amino acid sequence having at least 90% identity to SEQ ID NO: 2, or an amino acid sequence comprising or consisting of SEQ ID NO: 2; or (ii) a backbone protein, wherein the backbone protein comprises a consensus sequence having at least 90% sequence identity to SEQ ID NO: 4, and at least one heterologous Vibrio cholerae epitope. Appropriate clarification and/or correction is required.
Claim 28 is objected to because of the following informalities: the amendment to the claim recites a composition comprising a fusion protein or a nucleic acid. The nucleic acids are in Group II and the fusion proteins in Group I. Accordingly, the amended claim contains subject matter to a non-elected group which should be removed from the claim. Appropriate clarification and/or correction is required.
Claim Rejections - 35 USC § 112-2nd paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 6-12, 14, 28 (fusion protein), 29, 34, 39 and 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-3, 6-12, 14, 28, 29, 34, 39 and 40 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the claims is improper because the alternatives defined by the Markush grouping do not share both a substantial single structural similarity and a common use for the following reasons: the claims include completely different fusion proteins with different sequences and, accordingly, different immunogenic effects, raising different immune responses. The indicated size of the insertion or substitution is not limiting, and can be varied. These are not mere species of one another, but completely different fusion proteins/products. Additionally, claim 28 comprises two different products that are biologically, chemically and structurally distinct, e.g., nucleic acid and a protein. The Species Election Requirement mailed 10/23/25 recited:
For Group I:
Applicant must elect a single fusion protein, e.g, comprising a backbone protein at least 90% identical to SEQ ID NO: 4 and an epitope of SEQ ID NO: 31; OR
A fusion protein comprising SEQ ID NO: 2;
OR a e.g., comprising a backbone protein at least 90% identical to SEQ ID NO: 4 and an epitope of SEQ ID NO: 6 and 10; etc.
Applicants elected SEQ ID NO: 2, but the claims are not proper Markush groupings as stated above.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a substantial single structural similarity as well as a common use. It is maintained that the fusion proteins with different inserts are different products.
Claim 8 is vague and confusing because it is unclear how one determines the homologous V.cholerae epitope vs a heterologous V.cholerae epitope in the fusion protein. What is the protein homologous to? The metes and bounds of the invention cannot be readily understood. Appropriate clarification and/or correction is required.
Claim Rejections - 35 USC § 112-Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 6-12, 14, 28, 29, 34, 39 and 40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claim 1 recites:
A fusion protein comprising a backbone protein, wherein the backbone protein comprises a consensus sequence having at least 90% sequence identity to SEQ ID NO: 4, and at least one heterologous Vibrio cholerae epitope.
The instant specification fails to provide written support for variant backbone sequences. The claim allows for a 10% variation in the backbone, but it is unclear what amino acids could be removed and which could be added, and even more confusing with the breadth of different epitopes encompassed by the instant claims. The claim should be limited to a backbone protein that comprises or consists of SEQ ID NO: 4.
There is no teaching in the instant specification of which 10% can vary from SEQ ID NO: 4 (wherein there is already a great deal of variation allowed) and still result in a functional fusion polypeptide to induce an immune response to Vibrio cholerae. A representative number of species are not disclosed. There is no art-recognized correlation, e.g., conserved amino sequence, and recited activity. There is some general teaching in the art that some amino acid variations are tolerated without losing a protein’s tertiary structure, but conservation of structure in not necessarily a surrogate for conservation of function. While one of skill in the art could, with the aid of a computer as suggested, could identify all the amino acids that have at least 90% homology to the portion of SEQ ID NO: 4, this would not tell one the structure of the polypeptides having the recited functional activity. Accordingly, it does not appear applicants were in possession of the claimed sequences at the time of filing.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision (see page 115).
With the exception of SEQ ID NO: 4, the skilled artisan cannot envision the detailed structure of the encompassed polypeptide backbones and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and a reference to a potential method of isolating it. The polypeptide itself is required. See Fiers v. Revel, 25 USPQ 2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Lts., 18 USPQ2d 1016.
Furthermore, In The Reagents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that while Applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a representative number of DNA molecules, usually defined by a nucleotide sequence, falling within the scope of the claimed genus. At section B(1), the court states that "An adequate written description of a DNA...'requires a precise definition, such as by structure, formula, chemical name, or physical properties', not a mere wish or plan for obtaining the claimed chemical invention".
No disclosure, beyond the mere mention of backbone variants is made in the specification. Additionally, the claims are currently drawn to fusion proteins that comprise any of at least one homologous or heterologous V.cholera epitope. Or FlaB, CTA, CTB, etc. yet the specification fails to teach these specific sequences for all of the possible homologs or variants of these sequences, as some claims provide no sequence. Additionally, it is unclear where they could be asserted and in which combinations to provide the proper function. It is noted claim 14 when limited to a fusion protein comprising or consisting of the amino acid of SEQ ID NO: 2 has sufficient written support, but not variants of SEQ ID NO: 2.
Status of Claims
No claims are presently allowed.
Claims 1-3, 6-12, 14, 28 (fusion protein), 29, 34, 39 and 40; have been examined subject to the restriction that the claims read on a fusion protein comprising SEQ ID NO: 2.
The prior art does not teach or fairly suggest, individually or in combination, a fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO: 2.
The closest prior art is made of record:
(US 2020/0407404 A1) teaches a fusion protein comprising at least two Vibrio cholerae epitopes, wherein at least one of the two epitopes is from a different Vibrio cholerae serogroup or biotype (fusion proteins comprising an antigenic protein or peptide, Para. [0004]; an antigen is derived from an infectious microbe such as Vibrio cholera, Para. [0158]; an immunogenic composition as disclosed herein comprises at least 2 antigens the antigens can be. the same antigen which is specific to different serotypes or seasonal variations of the same pathogen, Para. [0093]; multiple protein antigens using single MAPS immunogenic construct, Para. [0128]).
(ii) Heidelberg et al "DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae" teaches an amino acid sequence having 67.3% sequence identity to instant SEQ ID NO: 2 (There are a total of 3,885 predicted open reading frames (ORFs) and 792 predicted Rho-independent terminators; with 2,770 and 1,115 ORFs and 599 and 193 Rho-independent terminators on the individual chromosomes (Table 1, Figs 1...), Pg. 478, left column, first partial paragraph; Figure 1 discloses VC2142; VC2142 of Heidelberg comprises 67.3% sequence identity to instant SEQ ID NO: 2). None of the prior art taken alone or in combination fairly teach or suggest a fusion protein comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 2, as recited above. Heidelberg et al "DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae" also teaches an amino acid sequence having 92.9% identity to Applicant’s SEQ ID NO: 4; but no heterologous sequences are present. The sequence is the same total length of Applicant’s SEQ ID NO: 4 and is identified as a flagellin protein from Vibrio cholera.
The closest prior art of record, individually or in combination, does not teach or fairly suggest a fusion protein comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 2.
Correspondence regarding this application should be directed to Group Art Unit 1645. Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center located in Remsen. The faxing of such papers must conform with the notice published in the Official Gazette, 1096 OG 30 (November 15,1989). The Group 1645 Fax number is 571-273-8300 which is able to receive transmissions 24 hours/day, 7 days/week.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Friday from 8:00 AM-4 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Thomas Visone, can be reached at (571) 270-0684.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-0500.
/JENNIFER E GRASER/ Primary Examiner, Art Unit 1645 4/23/26
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